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Crystal Engineering of Co-Crystals and Their Relevance to Pharmaceutical Forms Tanise R

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Crystal Engineering of Co-Crystals and Their Relevance to Pharmaceutical Forms Tanise R University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 2007 Crystal engineering of co-crystals and their relevance to pharmaceutical forms Tanise R. Shattock University of South Florida Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the American Studies Commons Scholar Commons Citation Shattock, Tanise R., "Crystal engineering of co-crystals and their relevance to pharmaceutical forms" (2007). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/2361 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Crystal Engineering of Co-Crystals and their Relevance to Pharmaceutical Forms by Tanise R. Shattock A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: Michael J. Zaworotko, Ph.D. Mohamed Eddaoudi, Ph.D. Edward Turos, Ph.D. Matthew L. Peterson, Ph.D. Date of Approval: July 16, 2007 Keywords: Supramolecular Chemistry, Supramolecular Synthon, Hydrogen Bond, Supramolecular Synthesis, Polymorphism © Copyright 2007, Tanise R. Shattock Dedication For Joshua Acknowledgements The author would like to express sincere gratitude and appreciation to her mentor and supervisor Dr. Michael J. Zaworotko for his support over the years and for all the opportunities he has made available for her professional growth and development. She would also like to thank Dr. Matthew L. Peterson, Dr. Mohamed Eddaoudi and Dr. Edward Turos, her committee members; Dr. Vishweshwar Peddy, Dr. Joanna Bis, Jennifer McMahon, Gregory McManus, Miranda Cheney, John J. Perry IV, Jason Perman and all members of the Zaworotko’s Research Group for all their help and advice. Words cannot adequately express her heartfelt appreciation to Nicholas and Joshua for their endless love, support, patience and understanding. Finally, she would like to acknowledge and thank her parents, her closest family and friends for their constant support throughout the years of studies. Table of Contents List of Tables ix List of Figures xi Abstract xvii Chapter 1. Introduction 1 1.1. Introduction 1 1.1.1. Supramolecular Chemistry 1 1.1.2. Intermolecular Interactions 2 1.1.3. Crystal Engineering 4 1.1.4. Supramolecular Synthons and the Cambridge Structural Database 5 1.1.5. Co-Crystal 8 1.1.6. Preparation of Co-Crystals 10 1.1.7. Pharmaceutical Co-Crystals 12 1.1.8. Polymorphism 21 1.1.9. Summary 23 1.2 References Cited 24 i Chapter 2. The Reliability of the Carboxylic acid-Aromatic Nitrogen Supramolecular Heterosynthon 39 2.1. Introduction 39 2.2. Results and Discussion 41 2.2.1. CSD Analysis 42 2.2.2.Features of Carboxylic Acid-Aromatic Nitrogen Interaction 45 2.2.3. Crystal Structure Description 50 2.3. Conclusions 67 2.4. Experimental Section 69 2.4.1. Co-crystallization via grinding 69 2.4.2. Co-crystallization via solvent-drop grinding 69 2.4.3. Co-crystallization via melting 69 2.4.4. Co-crystallization via solution evaporation 69 2.4.5. Crystal structure determination 73 2.5. References Cited 77 Chapter 3. The Reliability of the Alcohol−Aromatic Nitrogen Supramolecular Heterosynthon 83 3.1. Introduction 83 3.2. Results and Discussion 85 3.2.1. Cambridge Structural Database Analysis 85 3.2.2 Features of Hydroxyl···Aromatic Nitrogen Interaction 87 ii 3.2.3. Crystal Structure Description 90 3.3. Conclusions 100 3.4. Experimental Section 104 3.4.1. Synthesis of Co-Crystals 104 3.4.1. Co-crystallization via grinding 105 3.4.2. Co-crystallization via solvent-drop grinding 105 3.4.3. Co-crystallization via melting 105 3.5. References Cited 108 Chapter 4. Delineating the Hierarchy of Supramolecular Heterosynthons: Carboxylic acid-Aromatic Nitrogen versus Alcohol-Aromatic Nitrogen 113 4.1. Introduction 113 4.2. Results and Discussion 117 4.2.1.CSD Analysis 117 4.2.2 Features of the O-H⋅⋅⋅Narom interaction 119 4.2.3.Crystal Structure Descriptions 121 4.2.4 Methods of Preparation 145 4.3.Conclusions 147 4.4. Experimental Section 148 4.4.1.Syntheses 148 4.4.2. Single-crystal X-ray diffraction. 152 4.5. References Cited 156 iii Chapter 5. Pharmaceutical Co-crystals of Stavudine 160 5.1. Introduction 160 5.2. Results and Discussion 162 5.2.1. Crystal Structure Description 163 5.3. Conclusions 169 5.4. Experimental Section 170 5.4.1 Synthesis 170 5.4.2. Single-crystal X-ray diffraction 171 5.5. References Cited 176 6. Summary and Future Directions 180 6.1.Summary 180 6.2. Future Directions 184 Appendices 188 Appendix 1. Experimental Data for (benzoic acid)2• 1,2-bis(4-pyridyl)ethane 1 189 Appendix 2. Experimental Data for (benzoic acid)2 • trans-1,2-bis(4-pyridyl)ethylene 2 192 Appendix 3. Experimental Data for benzoic acid •4,4’-bipyridine, 3 195 Appendix 4. Experimental Data for sorbic acid• 1,2-bis(4-pyridinium)ethane sorbate 4 199 iv Appendix 5. Experimental Data for (naproxen)2 • trans-1,2-bis(4-pyridyl)ethylene 5 202 Appendix 6. Experimental Data for glutaric acid •1,2-bis(4-pyridyl)ethane, 6 205 Appendix 7. Experimental Data for glutaric acid• trans-1,2-bis(4-pyridyl)ethylene, 7 208 Appendix 8. Experimental Data for oxalic acid•tetramethylpyrazine, 8 211 Appendix 9. Experimental Data for isophthalic acid • 1,2-bis(4-pyridyl)ethane, 9 214 Appendix 10. Experimental Data for (trimesic acid)2 • trans-(1,2-bis(4-pyridyl)ethylene)3, 11 217 Appendix 11. Experimental Data for trimesic acid• 1,2-bis(4-pyridyl)ethane, 12 220 Appendix 12. Experimental Data for (1-naphthol)2 • 1,2-bis(4-pyridyl)ethane, 13 225 Appendix 13. Experimental Data for (1-naphthol)2 • trans-1,2-bis(4-pyridyl)ethylene, 14 227 Appendix 14. Experimental Data for 4,4’-biphenol • 1,2-bis(4-pyridyl)ethane, 15 229 Appendix 15. Experimental Data for 4,4’-biphenol • trans-1,2-bis(4-pyridyl)ethylene, 16 231 v Appendix 16. Experimental Data for hydroquinone • trans-1,2-bis(4-pyridyl)ethylene, 17 233 Appendix 17. Experimental Data for hydroquinone• tetramethylpyrazine, 18 235 Appendix 18. Experimental Data for (resorcinol)2•(TMP)3, 19 237 Appendix 19. Experimental Data for 2,7-dihydroxynaphthalene● (TMP)2, 20 239 Appendix 20. Experimental Data for (3-hydroxybenzoic acid)2 • pyrazine, 21 241 Appendix 21. Experimental Data for 4-hydroxybenzoic acid •1,2-bis (4-pyridinium)ethane • 4- hydroxybenzoate, 22 244 Appendix 22. Experimental Data for (4-hydroxybenzoic acid)2 • tetramethylpyrazine, 23 247 Appendix 23. Experimental Data for 4-hydroxybenzoic acid • 4-phenylpyridine, 24 249 Appendix 24. Experimental Data for (4-hydroxybenzoic acid)2 • pyrazine, 25 251 Appendix 25. Experimental Data for 4-hydroxybenzoic acid)2 • tetramethylpyrazine acetonitrile solvate, 26 254 Appendix 26. Experimental Data for 3-hydroxybenzoic acid • phenylpyridine)2, 27 256 Appendix 27. Experimental Data for 3-hydroxybenzoic acid • 1,2-bis(4-pyridyl)ethane, 28 259 vi Appendix 28. Experimental Data for 3-hydroxybenzoic acid • 4,4’-bipyridine, 29 262 Appendix 29. Experimental Data for 3-hydroxybenzoic acid • quinoxaline, 30 265 Appendix 30. Experimental Data for (3-hydroxybenzoic acid)2 • (tetramethylpyrazine)3, 31 268 Appendix 31. Experimental Data for 6-hydroxy-2-naphthoic acid • trans-1,2-bis(4-pyridyl)ethylene, 32 270 Appendix 32. Experimental Data for 4-hydroxybenzoic acid • trans-1,2-bis (4-pyridyl)ethylene, 33 272 Appendix 33. Experimental Data for 3-hydroxybenzoic acid • trans-1,2-bis(4-pyridyl)ethylene, 34 274 Appendix 34. Experimental Data for 3-hydroxypyridinium benzoate, 35 276 Appendix 35. Experimental Data for 3-hydroxypyridinium isophthalate, 36 279 Appendix 36. X-ray powder diffraction patterns of grinding and solvent drop grinding of isonicotinic acid •1-naphthol, nicotinic acid •1-naphthol, (nicotinic acid)2 •4,4’-biphenol, (isonicotinic acid)2 •4,4’-biphenol, (isonicotinic acid)3 •phloroglucinol, (nicotinic acid)3 •phloroglucinol, (isonicotinic acid)2 •resorcinol, (nicotinic acid)2 •resorcinol. 282 Appendix 37. Diffractograms of Melt Experiments 286 Appendix 39. Experimental Data for (stavudine)3 •melamine, 37 298 vii Appendix 40. Experimental Data for stavudine •2,4,6-triaminopyrimidine hydrate, 38 301 Appendix 41. Experimental Data for stavudine•2-aminopyridine, 39 303 Appendix 42. Experimental Data for stavudine•4-hydroxybenzoic acid, 40 307 Appendix 43. Experimental Data for stavudine• salicylic acid, 41 311 About the Author End Page viii List of Tables Table 1.1 Covalent and Non-covalent Interactions* 2 Table 1.2 Percentage Occurrence of hydrogen bonding functional groups in APIs 14 Table 2.1. Percentage occurrence, distance ranges, and average distance for supramolecular synthons I-VI 43 Table 3.1 Geometric features of supramolecular homosynthon V and supramolecular heterosynthon VI 86 Table 3.2 pKa values of components used in co-crystals 13-20 88 Table 3.3 Crystallographic data and structure refinement parameters for co-crystals 13-20 102 Table 3.4 Melting points of co-crystals 13-20 and corresponding starting materials 106 Table 3.5 Geometrical parameters of intermolecular interactions for co-crystals 13-20 107 Table 4.1 CSD statistics on supramolecular synthons that occur in structures containing only COOH, Narom, and OH 119 Table 4.2 pKa data for 21-36 121 Table 4.3 Summary of supramolecular synthons present in 21-36 145 Table 4.4 Melting point comparison for 21-36 147 ix Table 4.5 Hydrogen Bond Distances and Parameters for 21-36 154 Table 4.6 Hydrogen Bond Distances and Parameters for 21-36 (cont.) 155 Table 4.7 Crystallographic data and structure refinement parameters for compounds 21-36 156 Table 4.8 Crystallographic data and structure refinement parameters for compounds 21-36 (cont) 157 Table 5.1 Geometrical Features of Supramolecular Synthons 163 Table 5.2 Geometric Parameters of Intermolecular Interactions for (stavudine)3●melamine, 37 173 Table 5.3 Geometric Parameters of Intermolecular Interactions for 38-41 174 Table 5.4 Crystallographic Data and structure refinement parameters for compounds 37-41 175 x List of Figures Figure 1.1.
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